During the present funding cycle (09/01/01 to 08/31/06) we, GenoMEL, characterized the major effects of the known high penetrance melanoma susceptibility genes (cyclin dependent kinase [CDK] inhibitor 2A [CDKN2A] and CDK4) and increased understanding of interactions with lower penetrance genes, in particular MC1R. We also collected extensive data relating to geographic, environmental and phenotypic interactions. GenoMEL (www.genomel.org) was created in 1997;it brought together on an informal basis for exchange and promotion of melanoma science numerous international research groups interested in understanding the genetics of familial melanoma. In September 2001, funding was obtained from the NCI (this R01 CA83115) that served to underpin the fledgling, cooperative group. A successful application to the European Union for a Network of Excellence (NoE) "Framework 6" grant has ensured the viability of a considerably enlarged consortium by funding its administration and core data collection;as a result we have grown in effectiveness and size, with the recruitment of new participant groups in Utah, Toronto, Tel Aviv, Latvia, Poland, Slovenia and Queensland. This application for competitive renewal of the R01 will utilize the support of the members of GenoMEL and the European-based infrastructure established by the NoE funds to efficiently extend our exploration of the biological basis of susceptibility to melanoma and its application to risk assessment. This application will also support a large scale screening for identification of new high penetrance melanoma susceptibility genes. This application has two overarching objectives: Aim 1 is to determine the precise contribution of the CDKN2A locus to familial aggregation of melanoma and other cancers, and to develop tools which will enable clinicians to translate this information for use in counseling the population. We hypothesize that the prevalence and penetrance of CDKN2A mutations will vary strongly by region, by population, by population incidence, by the number and type of cancers in close relatives, and by covariates such as ethnicity, skin type, nevus phenotypes and sun exposure. Further, we hypothesize that specific classes of CDKN2A mutations differentially affect risk of melanoma, pancreatic and other cancers, as well as important intermediate phenotypes such as nevus count. We also hypothesize that current estimates of these parameters require validation because of concerns with respect to the effect of ascertainment;Aim 2 is to identify novel high-penetrance melanoma susceptibility genes. We hypothesize that other high penetrance melanoma susceptibility genes exist and that these encode members of the p16/CDK4/pRb and p14/MDM2/p53 pathways that have been previously implicated in melanoma susceptibility. Identification of additional high penetrance genes is important because our research to date has shown that 50% of families with 3+ cases of melanoma do not have mutations in CDKN2A and CDK4.